The surgical implantation of prosthetic devices (prostheses) into humans and other mammals has been carried out in recent years with increasing frequency. Such prostheses include, by way of illustration only, heart valves, vascular grafts, urinary bladders, left ventricular-assist devices, hip prostheses, silastic breast implants, tendon prostheses, and the like. They may be constructed from natural tissues, inorganic materials, synthetic polymers, or combinations thereof. By way of illustration, mechanical heart valve prostheses typically are composed of rigid materials, such as polymers, carbons and metals and employ one or more occluders which respond passively with changes in intracardiac pressure or flow. Natural tissue heart valve prostheses, on the other hand, typically are fabricated from either porcine aortic valves or bovine pericardium; in either case, the tissue is normally pretreated with glutaraldehyde and then sewn onto a flexible metallic alloy or polymeric stent which subsequently is covered with a poly(ethylene terephthalate) cloth sewing ring covering. Typically, the assembled prostheses (known to those of skill in the art as bioprostheses) are then stored in 0.2 percent glutaraldehyde.
Bioprostheses, that is prostheses derived from natural tissues, may be preferred over mechanical devices because of certain significant clinical advantages; for example, bioprostheses generally do not require routine anticoagulation. Moreover, when they fail, they usually exhibit a gradual deterioration which can extend over a period of months, or even years. Mechanical devices, on the other hand, generally require regular anticoagulation therapy and very occasionally undergo catastrophic failure; however, they do have other advantageous features.
Bioprostheses must be treated, prior to implantation into an animal different from the donor animal, in order to stabilize the tissue. This process of stabilization is known in the art as fixation. In 1968, Nimni et al. demonstrated that collagenous materials, the major component of bioprostheses, can be fixed by treating them with aldehydes. (Nimni et al., J. Biol. Chem. 243:1457-1466 (1968).) Later, it was discovered that, of various aldehydes tested, glutaraldehyde best retards degeneration of collagenous tissue. (Nimni et al., J. Biomed. Mater. Res. 21:741-771 (1987); Woodroof, E. A., J. Bioeng. 2:1 (1978).) Generally, the fixation process operates by blocking reactive molecules on the surface of and within the donor tissue, thereby rendering it substantially non-antigenic and suitable for implantation. Thus, the process of glutaraldehyde-fixation has been and continues to be applied to most all varieties of experimental and clinical bioprostheses.
Early experimental and clinical studies of glutaraldehyde-preserved bioprostheses were of bioprosthetic heart valves. The data compiled from these early studies demonstrated the excellent biomechanical properties, high resistance to enzymatic degradation, excellent hemodynamic properties and minimal thrombogenicity of the glutaraldehyde-preserved heart valve. However, follow-up clinical studies questioned the long-term durability of glutaraldehyde-fixed valves due to a variety of problems such as cuspal infection, low-grade immune reactions, severe calcification, stenosis and biodegradation. Further, it was discovered that the glutaraldehyde-fixation process induces toxic reactions due to the slow release of glutaraldehyde from the implanted tissue. These toxic reactions may be partially responsible for the immune reactions and the lack of endothelial cell coverage also found in these implants.
Calcification, which causes prosthesis degeneration, is an especially significant disadvantage to the use of tissue-derived prostheses. Indeed, cuspal calcification accounts for over 60 percent of the failures of cardiac bioprosthetic valve implants, such failures being substantially more frequent in children than in adults. Despite the clinical importance of the problem, the pathogenesis of calcification is incompletely understood. It seems that calcification is related to the extent of glutaraldehyde-induced cross-links and results from intrinsic and extrinsic mineralization in and on the surface of the bioprosthesis. (Schoen, F., J. Card. Surg. 2(1):65 (1987).) Further there is evidence of a specific calcium-binding amino acid, laid down after implantation of glutaraldehyde-preserved porcine bioprostheses, which has been postulated to play a role in calcification.(U.S. Pat. No. 4,770,665)
Efforts at retarding the calcification of bioprosthetic tissue have been numerous in recent years. The techniques resulting from these efforts may be broadly divided into two categories; those involving the pre- or post-treatment of glutaraldehyde-fixed tissue with one or more compounds that inhibit calcification (or modify the fixed tissue to be less prone to calcification) and those involving the fixation of the tissue with compounds other than glutaraldehyde, thereby reducing calcification.
The former category of techniques includes, but is not limited to, treatment with such compounds as:
a) detergent or surfactant, after glutaraldehyde fixation;
b) diphosphonates, covalently bound to the glutaraldehyde-fixed tissue or administered via injection to the recipient of the bioprosthesis or site-specifically delivered via an osmotic pump or controlled-release matrix;
c) amino-substituted aliphatic carboxylic acid, covalently bound after glutaraldehyde-fixation;
d) sulfated polysaccharides, especially chondroitin sulfate, after glutaraldehyde fixation and preferably followed by treatment with other matrix-stabilizing materials;
e) ferric or stannic salts, either before or after glutaraldehyde fixation;
f) polymers, especially elastomeric polymers, incorporated into the glutaraldehyde-fixed tissue; or
g) water-soluble solutions of a phosphate ester or a quaternary ammonium salt or a sulfated higher aliphatic alcohol, after glutaraldehyde-fixation.
The latter category of techniques for reducing the calcification of bioprosthetic tissue, i.e., techniques involving the fixation of the tissue with compounds other than glutaraldehyde, includes but is not limited to, the following:
a) treatment by soaking the bioprosthetic tissue in an aqueous solution of high osmolality containing a photo-oxidative catalyst and then exposing said tissue to light, thereby fixing the tissue via photo-oxidization; and
b) fixation via treatment with a polyepoxy compound, such as polyglycidyl ether (polyepoxy) compound.
In most cases, investigations related to glutaraldehyde-associated symptomatology have been limited to specific problems such as calcification and have not addressed the entire spectrum of symptoms. Thus, while the problem of calcification of glutaraldehyde-fixed bioprostheses has received a great deal of attention, the proposed solutions have generally failed to address any other complications presented by the presence of glutaraldehyde, such as toxicity, immune reactions and degeneration. Glutaraldehyde released from the tissue is cytotoxic and prevents the formation of endothelial cell growth on the bioprosthesis necessary for long-term durability. This persistent damage to the implant and surrounding tissue due to the long-term slow release of glutaraldehyde may be fully eradicated only by using a fixation process that does not include glutaraldehyde. The complexity and gravity of the clinical problems resulting from glutaraldehyde-preserved bioprostheses warrant the search for an alternative fixation method.